Protein prenylation is a critically important post-translational modification process. It is required for the proper membrane association and activity of many signal transduction proteins, including the Ras oncogene products. Farnesyltransferase inhibitors have been the objects of intense interest as anti-cancer agents, and promising results have been observed with these compounds in certain clinical trials. Recent genetic knockout studies have indicated that the closely related enzyme GGTase I may also be an intriguing anti-cancer drug target. The long-term goal of this research project is the development of chemical tools for the selective modulation of protein prenylation. These probes will allow for the determination of the relative roles of various prenylated proteins in cancer cell growth. During the previous grant period, we provided significant new data in support of the specific hypothesis that the unique structure and mechanism of FTase allows for the discovery of selective FPP analogs that will prenylate certain FTase substrate proteins, but not others. This has placed us in a position to investigate the long-term hypothesis: the subcellular localization and biological activity of prenylated proteins can be altered by their selective modification with unnatural prenyl groups. This goal will be accomplished through a) the development of new chemical tools; b) their biochemical evaluation; c) their cellular evaluation; and d) the demonstration of their ability to modulate the activity of the key oncoprotein Ras in cellular settings.